tbuckley/cabot-search huggingface dataset:
Abstract 4298: Machine learning-based model for survival prediction after immunotherapy in patients with solid tumor
Authors: Salma Y. Fala, Mohamed Osman
Journal: Cancer Research (2023)

Abstract Background: Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in solid tumors treatment. However, not all patients respond favorably to these drugs, highlighting the need for reliable predictions to achieve more personalized care and better management. This study aimed to create and validated ML model to predict survival in solid tumors patients receiving ICIs. Methods: We obtained clinical and genomic data from cBio Cancer Genomics Portal. Data were randomly divided into a training set (80%) and a validation set (20%). light gradient boosting algorithm was trained to predict patients’ survival at different time points. Results: We identified 1660 patients with a median survival of 18 months. LGB yielded AUCs of 67.91% at 1 year, 79.89.6% at 2 years, and 79.75% at 3 years, respectively. The most important predictors that influenced the performance of the model in predicting 3-year-survival were: Age (22.89%), tumor mutational burden (18.24%), and tumor purity (13.23%). Moreover, multivariate analysis was performed and drug type was identified as an independent prognostic indicator (P&amp;lt; .001). So, a Subgroup analysis was done and the OS rates were: 98.57%, 75.55%, 33.84% in patients who received CTLA-4, 98.57%, 75.55%, 33.84% with PD-1/PD-L1, and 97.99%, 9.94%, 4.62% with combo treatment, at 1-, 3-, and 5 years, respectively. Conclusion: Our ML-based model that integrates both clinical and genomic data is an improved tool for survival prediction, enabling an accurate risk classification and leading to a more precise decision-making. Moreover, this study highlights the importance of age and tumor microenvironment as the main contributors in making survival prediction in patients receiving ICIs. Table. Performance in survival prediction among training and testing sets Table 1. Survival Average AUC Average Accuracy Survival Duration Positive Predictive Value (Precision) Sensitivity (Recall) 1-year 67.91% 63.18% &amp;lt;12 months 58% 54% &amp;gt;=12 months 67% 70% 2-years 79.89% 78.70% &amp;lt;24 months 86% 84% &amp;gt;=24 months 62% 65% 3-years 79.75% 86.02% &amp;lt;36 months 95% 89% &amp;gt;=36 months 45% 65% Citation Format: Salma Y. Fala, Mohamed Osman. Machine learning-based model for survival prediction after immunotherapy in patients with solid tumor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4298.
Abstract 2555: 14-3-3 and Smad2/3 are key mediators of atypical-PKCs in neuroblastoma progression
Authors: Sloan Breedy, Wishrawana S. Ratnayake, Luke Lajmi, Robert Hill, Mildred Acevedo-Duncan
Journal: Cancer Research (2023)

Abstract Neuroblastoma (NB) is a cancer that develops in the neuroblasts. It is the most common cancer in children under the age of 1 year, accounting for approximately 6% of all cancers. The prognosis of NB is linked to both age and degree of cell differentiation. This results in a range of survival rates for patients, with outcomes ranging from recurrence and mortality to high survival rates and tumor regression. Our previous work indicated that PKC-ι promotes cell proliferation in NB cells through the PKC-ι/Cdk7/Cdk2 cascade. We report on two atypical protein kinase inhibitors as potential therapeutic candidates against BE(2)-C and BE(2)-M17 cells: a PKC-ι-specific 5-amino-1-2,3-dihydroxy-4-(methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and a PKC-ζ specific 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat). In the current study, we report the effects of aPKC inhibition on 14-3-3-centered signaling in NB progression. To this end we utilized various techniques such as western blotting, Flowcytometry, scratch assays and invasion assays. These assays were employed to assess the downstream implications of aPKCs and 14-3-3 attenuation on signaling pathways regulating proliferation, cell cycle regulation, apoptosis, and metastasis. Both compounds induced apoptosis and retarded the epithelial-mesenchymal transition (EMT) of NB cells. Proteins 14-3-3 and Smad2/3 acted as central regulators of aPKC-driven progression in BE(2)-C and BE(2)-M17 cells in relation to the Akt1/NF-κB and TGF-β pathways. We demonstrate the downstream effects of aPKC attenuation on aPKC phosphorylation, the Akt1/NF-κB pathway, the Cdk7/Cdk2 pathway and EMT in relation to 14-3-3 and Smad2/3. We have analyzed the expression of EMT markers including Vimentin, a mesenchymal marker that is a hallmark of cancer metastasis. Data indicates that aPKCs upregulate Akt1/NF-κB and TGF-β pathways in NB cells through an association with 14-3-3 and Smad2/3 that can be diminished by aPKC inhibitors. In summary, both inhibitors appear to be promising potential neuroblastoma therapeutics and merit further research. Citation Format: Sloan Breedy, Wishrawana S. Ratnayake, Luke Lajmi, Robert Hill, Mildred Acevedo-Duncan. 14-3-3 and Smad2/3 are key mediators of atypical-PKCs in neuroblastoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2555.
Abstract 3750: miR-590-3p inhibits multiple oncogenic nodes within the TGFBR2:SMAD2/3 pathway in recurrent GBM cells
Authors: Sophie Sall, Jack Korleski, Amanda Johnson, Maya Johnson, Hernando Lopez-Bertoni
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is the most lethal and aggressive primary brain malignancy with high recurrence rates and virtually no long-term survival. Despite our expanding knowledge regarding GBM at the genomic/molecular level, we still don’t fully comprehend the molecular mechanisms responsible for GBM recurrence. Current knowledge implicates tumor-propagating Glioma Stem Cells (GSCs) in the evolution of treatment resistance and tumor recurrence. Understanding these cellular/molecular events will inform strategies for preventing and/or treating recurrent GBM (rGBM). Gene set enrichment analysis (GSEA) of RNA sequencing datasets obtained from GSCs and clinical rGBM specimens identified TGFBR2 signaling as a high frequency and potentially targetable pathway in rGBM. We show that SMAD2/3 signaling, a downstream effector of TGFBR2, is enriched in rGBM and that patients with elevated TGFBR2 have statistically shorter long-term survival outlooks. The functional relevance of these findings was supported using ITD1, a selective TGFBR2 inhibitor, which decreased the GSC phenotype and cell viability of cells derived from clinical rGBM (rGBM cells), while simultaneously re-sensitizing them to temozolomide (TMZ) in-vitro. Since GBM is known to efficiently develop resistance to receptor-targeting monotherapies, we sought to simultaneously target multiple putative oncogenic drivers downstream of TGFBR2. To achieve this, we applied an unbiased miRNA-based network analysis that identified miR-590-3p as an inhibitor of SMAD2/3 signaling at multiple nodes and thus a potential tumor suppressor in rGBM. Transgenic miR-590-3p robustly decreased the expression of &amp;gt;30 putative oncogenes, reduced the GSC phenotype and cell viability, as well as re-sensitized rGBM cells to TMZ. These results predict that blocking TGFBR2 signaling will negatively impact the tumor phenotype of rGBM as well as its GSC capacity. Ongoing directions for this research include comparing the efficacy of ITD1 monotherapy with miR-590-3p therapy in rGBM models in-vivo. These results identify a significant role of TGFBR2 signaling in both TMZ resistance and the GSC phenotype in rGBM and provide a miRNA-based strategy for simultaneously targeting multiple oncogenic nodes within the TGFBR2 and potentially other oncogenic signaling pathways. Citation Format: Sophie Sall, Jack Korleski, Amanda Johnson, Maya Johnson, Hernando Lopez-Bertoni. miR-590-3p inhibits multiple oncogenic nodes within the TGFBR2:SMAD2/3 pathway in recurrent GBM cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3750.
Abstract 5727: Identification of synthetic lethal vulnerabilities in cancers with loss of function mutations in NOTCH
Authors: Deli Hong, Matthew A. Booker, Sidrah Anjum, Yixiang Li, Tran C. Thai, Michelle Y. Wang, David A. Barbie, Michael Y. Tolstorukov, Jun Qi, Matthew G. Oser
Journal: Cancer Research (2023)

Abstract Loss of Function (LOF) mutations in the NOTCH receptors are found in several different cancers most notably in small cell lung cancer (SCLC) and squamous cell carcinomas (SCC). We previously developed genetically engineered mouse models (GEMM) of SCLC using CRISPR/Cas9 engineered to be NOTCH1-Mutant, NOTCH2-Mutant, and NOTCH-WT. Synthetic lethality provides a paradigm for targeting cancers with LOF mutations in tumor suppressor genes. In applying this paradigm, one looks for specific vulnerabilities that are created upon loss of the gene of interest. Using 6 cell lines developed from these CRISPR-based SCLC GEMMs which are isogenic to NOTCH, we performed CRISPR/Cas9 LOF negative selection screens (using an sgRNA library enriched in druggable enzymes) to identify synthetic lethal interactors with LOF NOTCH mutations. Our CRISPR/Cas9 screen identified TRIM28 (Tripartite Motif Containing 28, or KAP1) as a highly significant synthetic lethal interactor with NOTCH1 or NOTCH2. We validated the synthetic lethal interaction between NOTCH1/2 and TRIM28 using both human and mouse NOTCH-isogenic cell lines. Interestingly, RNA-sequencing of NOTCH2-Mutant or NOTCH-WT SCLC cell lines after TRIM28 CRISPR inactivation showed robust increases in endogenous retroviral (ERV) expression and the MDA5/RIG-I/MAVS RNA-sensing machinery leading to hyperactivation of the TBK1/IRF3/7 innate immune signaling pathway and the pro-inflammatory cytokine CXCL10 selectively in cells with NOTCH inactivated. Notably, inactivation of TBK1 activity or JAK-STAT activity using specific small molecule inhibitors of TBK1 or JAK completely reversed the synthetic lethality between NOTCH and TRIM28 suggesting that the synthetic lethality phenotype is a consequence of hyperactivation of innate immune signaling, which is known to be cytotoxic. Together our findings uncover a novel vulnerability in SCLCs with LOF NOTCH mutations and perhaps other cancers with LOF NOTCH mutations and suggest a strategy that could also potentiate anti-tumor immunity by increasing innate immune signaling in tumor cells. Citation Format: Deli Hong, Matthew A. Booker, Sidrah Anjum, Yixiang Li, Tran C. Thai, Michelle Y. Wang, David A. Barbie, Michael Y. Tolstorukov, Jun Qi, Matthew G. Oser. Identification of synthetic lethal vulnerabilities in cancers with loss of function mutations in NOTCH. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5727.
Abstract 2238: RAS activity-related features of metastatic pancreatic cancer
Authors: Shuichi Mitsunaga, Mari Masuda, Hiroki Yoshimatsu, Yoichi Kamei, Mitsuhito Sasaki, Kazuo Watanabe, Masafumi Ikeda
Journal: Cancer Research (2023)

Abstract Background: RAS activity might play crucial roles in the aggravation of KRAS-mutated pancreatic cancer (PC), including systemic inflammatory reactions, tumor-driven inflammation, chemo-refractoriness and anorexia. We aimed to identify RAS activity-related features in PC patients with liver metastasis (LM), to create a murine xenograft model of human PC cells representative of RAS-driven aggravation. Methods: RAS activities in 77 patients who underwent needle biopsy for LM of treatment-naïve PC were measured using an RAS signature score from a comprehensive cDNA microarray dataset of LM samples. Changes in the sum of the longest diameter of the target lesion in the first month of chemotherapy (ΔSLD), laboratory data and anorexia score at baseline were evaluated. Gene modules to be correlated with RAS activity and aggravation were evaluated using weighted co-expression network analysis (WGCNA). Human PC cells were classified as high and low activity according to in silico analysis of the DepMap CCLE expression dataset for profiling RAS activity and the best hub gene expression in the gene module. Subcutaneous xenograft models of human PC cells with high and low activity in severe combined immunodeficiency mice were compared to explore the RAS-related phenotype. Results: KRAS-mutated LM was detected in 70 of the 77 PC patients (90.9%). RAS signatures were up-regulated in patients with KRAS-mutated LM (P &amp;lt; 0.01), high serum level of C-reactive protein (P = 0.01) as a systemic inflammatory marker, high expression of IL-6 mRNA by the tumor (P = 0.12) as an index of tumor-driven inflammation, and high level of phospho-Erk (P = 0.03). In 58 PC patients receiving first-line chemotherapy for KRAS-mutated LM, ΔSLD in patients with a high RAS signature was increased as compared to those in patients with a low RAS signature (P = 0.045). WGCNA methods revealed that the green module highly correlated with RAS activity and aggravation. Based on in silico analysis with classification of the human PC cell lines CFPAC-1 and SUIT-2 into high and low activity cells, respectively, CFPAC-1 tumors showed desmoplasia and high expression of tumor IL-6 and liver SAA1 as compared to SUIT-2 tumors (P = 0.046 and P = 0.016, respectively). Conclusions: Tumor RAS activity is related to inflammation-related aggravation in PC patients. RAS-related inflammation can be accurately presented in a murine model of human PC cells, which might be an effective tool to test the inhibition of RAS-driven inflammation. Citation Format: Shuichi Mitsunaga, Mari Masuda, Hiroki Yoshimatsu, Yoichi Kamei, Mitsuhito Sasaki, Kazuo Watanabe, Masafumi Ikeda. RAS activity-related features of metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2238.
Abstract 5620: Radiogenomic analysis in the patients with primary brain tumor using dual time point 18F-FET PET/CT
Authors: Dong Yun Lee, Sang Woo Song, Seungjoo Lee, Minyoung Oh, Jungsu S. Oh, Jaeseung Kim
Journal: Cancer Research (2023)

Abstract Purpose: To evaluate the association between genomic data and imaging features of dual time point 18F-FET PET/CT in patients with primary brain tumor for radiogenomic mapping. Methods: From June 2021 to July 2022, we prospectively enrolled the patients under suspicious of de novo primary brain tumor in Asan Medical Center. Prior to the surgery, contrast-enhanced MRI and 18F-FET PET/CT scans were routinely performed. Twenty minutes after the post-injecting (p.i.) approximately 5 mCi of 18F-FET, patients underwent early PET/CT acquisition (20-40 min p.i.). Delay PET/CT (80-100 min p.i) was subsequently obtained after 40-minute break. SUVmax, maximum tumor-to-brain ratios and PET-positive volumes using different isocontours of SUVmax (I30, I60, I90%) in tumor were calculated in each sum images. Histopathologic results were made based on 2016 WHO classification and, isocitrate dehydrogenase (IDH) mutation, O6-methylguanine-DNA methyltransferase (MGMT) methylation, telomerase reverse transcriptase (TERT) mutation and co-deletion of 1p19q status were investigated as well. Spearman’s correlation coefficient (r), logistic regression and AUC-ROC analysis were employed using aforementioned radiomics information. Results: A total of 42 patients (median age 55.5 yrs, range 21-84; M:F=31:11) were recruited and, 29 patients had glioblastoma with grade IV. Except TERT mutation (n=25), IDH mutation (n=11), MGMT methylation (n=19) and co-deletion of 1p19q (n=8) had statistically significant correlation each other (IDH vs. MGMT, r=0.55; IDH vs. 1p19q, r=0.53; MGMT vs. 1p19q, r=0.42). Early scan of I60% was closely related with IDH mutation (positive, 3.92 ± 3.04 vs. negative, 7.96 ± 5.36; p=0.005) meanwhile delay scan of I30% had significant association with co-deletion of 1p19q (present, 34.16 ± 18.67 vs. absent, 71.99 ± 38.79; p=0.01). The accuracy of logistic regression and the corresponding AUC-ROC values for IDH/MGMT/TERT/co-deletion of 1p19q status were 0.86/0.73/0.78/0.85, and 0.88/0.76/0.78/0.91, respectively. Conclusion: Although this is a preliminary and interim analysis during our prospective study being slated to enroll the patients until December 2023, we suggest that the information acquired from both genetics and 18F-FET could be integrated into better characterization of primary brain tumor. Citation Format: Dong Yun Lee, Sang Woo Song, Seungjoo Lee, Minyoung Oh, Jungsu S. Oh, Jaeseung Kim. Radiogenomic analysis in the patients with primary brain tumor using dual time point 18F-FET PET/CT. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5620.
Abstract 16: The role of innate and adaptive immunity in the sex bias of LKB1-mutant lung adenocarcinoma
Authors: Yijian Fan, Lenore Monterroza, Rui Jin, Xiuju Liu, Periasamy Selvaraj, Rabindra Tirouvanziam, Wei Zhou
Journal: Cancer Research (2023)

Abstract The tumor suppressor gene, LKB1/STK11, is one of the most frequently mutated genes in lung adenocarcinoma (LUAD). A multidimensional analysis of TCGA-LUAD patient data indicates that LKB1 mutation is one of the top sex-biased mutations, being more frequent in males than in females. A similar pattern was observed in other large LUAD cohorts. However, the underlying mechanism was unknown, partially due to a lack of an appropriate mouse model to represent this clinical phenomenon. We previously demonstrated a similar sex bias in a Lenti-Cre-induced KRAS/LKB1-mutant genetically engineered mouse model (GEMM) and a syngeneic tail-vein injection model. Here, we demonstrated that intravenous injection of the same cell line in male and female NOD scid gamma (NSG) mice does not exhibit a sex-bias pattern of lung metastasis formation (P=0.9746). However, sex bias was observed when we used CB17-SCID mice. This data suggest that innate immunity is partly responsible for the sex bias of LKB1-mutant lung cancer formation. We also characterized immune cells from the lung with LKB1-mutant tumors. Monocytes/macrophages decreased from 23% to 19%, and neutrophils increased from 15% to 19%. Lymphoid cells remained the same at 58%, and T-cells account for 34% of all CD45+ cells. Interestingly, T-cells doubled to account for 81% of all CD45+ cells from the lung in female mice resistant to the formation of lung metastasis. Our data indicated that both the innate and the adaptive immunity are responsible for eliminating LKB1-mutant lung adenocarcinoma in female mice. Citation Format: Yijian Fan, Lenore Monterroza, Rui Jin, Xiuju Liu, Periasamy Selvaraj, Rabindra Tirouvanziam, Wei Zhou. The role of innate and adaptive immunity in the sex bias of LKB1-mutant lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 16.
Abstract 4925: Cannabidiol and <i>Cannabis Sativa</i> as a potential treatment in vitro prostate cancer cells silenced with RBBp6 and PC3 xenograft
Authors: Lesetja Raymond Motadi, Zodwa E. Jantjies
Journal: Cancer Research (2023)

Abstract Background: Prostate cancer is the second most frequently occurring carcinoma in males worldwide and one of the leading causes of death in men around the world. Recent studies estimate that over 1.4 million males are diagnosed with prostate cancer on an annual basis, with approximately 375 000 succumbing to the disease annually. With current treatments continuing to show severe side effects, there is a need for new treatments. In this study we looked at the effect of cannabis sativa extract, cannabidiol and cisplatin on prostate cancer cells, PC3. Methods: In addressing the above questions, we employed the MTT assay to measure the antiproliferative effect on PC3 cells following treatment with varying concentrations of Cannabis sativa extract, cisplatin and cannabidiol. xCELLigence was also used to confirm the IC50 activity in which cells were grown in a 16 well plate coated with gold and monitor cell attachment. Caspase 3/7 activity was also measured using 96 well-plate following treatment. Western-blot and qRT-PCR was also used to measure the gene expression of tumor suppressor genes, p53, Bax and Bcl2. Animal studies were employed to measure the growth of PC3-mouse derived cancer to evaluate the effect of compounds in vivo. Results: From the treatment with varying concentrations of Cannabis sativa extract, cannabidiol and cisplatin, we have observed that the three compounds induced antiproliferation of PC3 cancer cell lines through the activation of caspase 3/7 activity. We also observed induction of apoptosis in these cells following silencing of retinoblastoma binding protein 6 (RBBP6), with upregulation of p53 and bax mRNA expression, and a reduction in Bcl2 gene expression. The growth of tumors in the mouse models were reduced following treatment with cisplatin and cannabidiol. Conclusion: We demonstrated that cannabidiol is a viable therapy to treat prostate cancer cells, in combination with silencing of RBBP6. This suggests that cannabidiol rather Cannabis sativa extract may play an important role in reducing cancer progression. Citation Format: Lesetja Raymond Motadi, Zodwa E. Jantjies. Cannabidiol and Cannabis Sativa as a potential treatment in vitro prostate cancer cells silenced with RBBp6 and PC3 xenograft. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4925.